Hemostatic reaction is one of the most important protection mechanisms in the living body. It generally consists of primary hemostasis wherein platelets adhere and agglutinate to impaired portions of the blood vessel and secondary hemostasis wherein soluble fibrinogens are transformed into insoluble fibrins to plug the impaired portions. The process of secondary hemostasis is accomplished by successive reactions known as a blood coagulation cascade by a variety of blood coagulation factors and cofactors and has two courses, the intrinsic and extrinsic coagulation pathways (FIG. 1). Thus, if any factor or cofactor in the blood coagulation cascade is deficient or does not work properly, blood coagulation is hindered to lead hemorrhage. In most of these diseases, genetic disposition is traced and typical diseases caused by congenital disorder in blood coagulation factors are hemophilia A and B, deficient in Factor VIII and Factor IX, respectively.
For treating patients suffering from hemophilia, there have been developed concentrated preparations that comprise Factor VIII or Factor IX for supplement of the deficient factors and are used for hemostatic management, known as supplemental therapy. However, it is known that antibodies against Factor VIII or Factor IX, usually referred to as “inhibitors”, are produced in about 2 to 24% of the patients subject to supplemental therapy (Thromb. Haemost. 67: 600-602 (1992); Int. J. Hematol. 62: 175-181 (1995); Lancet 339 (8793): 594-598 (1992); and Blood 83: 2428-2435 (1994)), which is one of the most serious side effects of supplemental therapy. Once inhibitors are produced in patients, supplemental therapy becomes ineffective to lead to extreme difficulty in hemostatic management. There are also many reports as to inhibitors that are induced spontaneously or in a way of autoimmune disease even in the absence of genetic disposition such as hemophilia (Thromb. Haemost. 45: 200-203 (1981)).
Principal therapies currently used for treating patients who possess inhibitors are as follows:
(a) Neutralizing Therapy:
An overdose of concentrated preparations that surpasses inhibitors is administered to neutralize inhibitors and factors necessary for hemostasis are supplemented.
(b) By-pass Therapy
As Factor VIII and Factor IX are both involved in the intrinsic coagulation pathway, hemostasis is effected not through (i.e. “bypassing”) the intrinsic coagulation pathway but by the extrinsic coagulation pathway. For enhancement of capacity of the extrinsic coagulation pathway, activated prothrombin complex concentrate, called “APCC”, or FVIIa preparations are administered.
(c) Immune Tolerance Therapy
Concentrated preparations are administered at high dose in a long spell so that ability of patients to produce inhibitors becomes immunologically impoverished, leading to disappearance of the antibodies.
However, the conventional therapies as mentioned above hold disadvantages in several points. Neutralizing therapy (a) is only efficacious to patients with a lower. titer of inhibitors but ineffective to patients with a higher titer of inhibitors.
In by-pass therapy (b), APCC has been reported to cause side effects such as myocardial infarction (Am. J. Med. 85: 245-249 (1988)) or DIC (Thromb. Haemost. 48: 339-340 (1982)) to raise safety problem. On the other hand, FVIIa preparations are disadvantageous in that it must be administered frequently due to short half-life of FVIIa (Transfus. Med. Rev. 7: 78-83 (1993)), charging patients with much burden physically as well as economically for high cost of the drug. Moreover, FVIIa preparations are not sufficiently efficacious. Immune tolerance therapy (c) can only be efficacious to a limited number of patients and also charges economical burden to patients.
As such, the conventional methods for hemostatic management of patients who possess inhibitors are not sufficiently efficacious and hence there exist needs for preparations that are safer, more efficacious, and easy for hemostatic management.
Prior art includes Japanese patent publication Nos. 145072/1995 to 145075/1995 entitled “Aqueous Composition for Treatment of Blood Coagulation Factor Inhibitor” wherein an activation level in the conventional APCC is explored but active substances responsible for bypassing activity is not clarified. Another prior art is Japanese patent publication No. 110715/1997 entitled “Pharmaceutical Composition for Treatment of Blood Coagulation Disorders and Process for Preparation thereof” wherein a content of FVIIa in the APCC is increased so that a treatment efficacy is enhanced. This composition, however, is merely addition of FVIIa that is confirmed to be efficacious when used alone to the APCC and hence still holds drawbacks as mentioned above.